Rapid advances in nanotechnology will be accompanied by the exposure of millions of individuals to products containing nanomaterials. Carbon Nanotubes (CNTs) are a major type of engineered nanomaterial designed and modified at the atomic level for multiple uses (electronics, engineering, medicine). While there are many beneficial uses for CNTs, there is also strong evidence that they cause lung injury and respiratory disease in mice and rats. A major concern is that CNTs have some properties similar to asbestos, a fiber that is linked with the development of pulmonary fibrosis (tissue scarring) and mesothelioma (a rare cancer on the pleural surface of the lung). We discovered that inhaled CNTs migrate to the pleura (the sensitive mesothelial lining surrounding the lungs) in mice to cause pleural injury and inflammation. We have also reported that CNTs increase pulmonary fibrosis in mice pre-exposed to allergens or bacterial lipopolysaccharide. It is paramount to understand how CNTs cause respiratory diseases in mice, especially fibrosis and cancer, before human exposures become widespread and identify susceptibility factors to clearly evaluate risk. The overall goal of this proposal is to elucidate CNT toxicity using genetically engineered mouse models of susceptibility to specific respiratory diseases; specifically pulmonary fibrosis, and mesothelioma. We further seek to determine whether selective surface coatings achieved by atomic layer deposition (ALD), a novel technique of engineering nanoscale structures, affect the potential of CNTs to mitigate or exacerbate these respiratory diseases. The specific hypothesis to be tested in this proposal is that susceptibility to CNT-induced pulmonary fibrosis and mesothelioma is due to reduced expression or impaired functional interaction between COX-2, STAT-1, and p53. The following specific aims will be carried out to test this hypothesis: In Aim 1, we will determine whether COX-2 mediates increased p53 levels after exposure to ALD-CNTs and whether COX-2 deletion reduces p53 levels in the lungs of exposed mice to cause fibrosis or mesothelioma. In Aim 2, we will determine whether STAT-1 activation induces and activates p53 after exposure to ALD-CNTs and whether STAT-1 deletion reduces p53 in the lungs of exposed mice to cause fibrosis or mesothelioma. In Aim 3, we will determine whether p53-deficient mice are susceptible to pulmonary fibrosis or develop mesothelioma after exposure to CNTs and whether ALD modification of CNTs alters disease outcome. In Aim 4, we will determine whether ALD-modified CNTs activate MAPKs via ROS as a proximal signal to induce COX-2, STAT-1, or p53, and whether loss of COX-2, STAT-1, or p53 amplifies CNT-induced MAPK signaling. This novel approach will provide valuable information on mechanisms through which CNTs cause respiratory diseases. Moreover, we will identify specific genes whose deficiency will put individuals at greater risk resulting from CNT exposure. Our approach also takes advantage of an innovative cross-disciplinary approach to specifically modify the surface chemistry of carbon nanotubes to determine whether toxicity and disease susceptibility are increased or decreased. The new insights into the molecular mechanisms through which CNTs promote chronic lung disease in mice will improve our understanding of susceptibility to specific types of lung disease. The broad impact of this work will directly affect the health and well-being of millions of individuals in the U.S. and worldwide by providing essential information for the design of safer nanomaterials. PUBLIC HEALTH RELEVANCE: Carbon nanotubes are considered one of the most promising materials in nanotechnology and have numerous applications in industry and consumer products. For many of these applications, nanotubes will be coated with various organic or inorganic agents to modify their surface chemistry. While the human health risks to carbon nanotubes is unknown, exposures to carbon nanotubes will inevitably occur due to increased production for a variety of uses in structural engineering, electronics, and medicine. Experimental evidence from laboratories worldwide indicates that carbon nanotubes cause chronic respiratory diseases in mice and rats. Therefore, it is imperative that we determine mechanisms of disease susceptibility in mice to better predict the relative risk to human health.